Structural changes of fibrinogen as a consequence of cirrhosis

Gligorijević, Nevenka; Minić, Simeon; Križáková, Martina; Katrlı́k, Jaroslav; Nedić, Olgica

doi:10.1016/j.thromres.2018.04.005

Cited by 13 publications

(13 citation statements)

References 55 publications

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“…(61) This could be due to underlying inflammation, as fibrinogen is an acute-phase protein. (64,65) Fibrinogen could also undergo structural modifications, leading to functional alterations in LC. (66) One cause of thrombin time prolongation in LC is an impaired polymerization of fibrin monomers.…”

Section: Fibrinogenmentioning

confidence: 99%

“…(66) One cause of thrombin time prolongation in LC is an impaired polymerization of fibrin monomers. (67) Several studies have reported increased sialic acid (SA) content of fibrinogen in LC (64,67) and a correlation between increased SA content of fibrinogen and prolonged thrombin time. (68) A possible explanation for the increased SA content of fibrinogen is an enhanced sialyl-transferase activity.…”

Section: Fibrinogenmentioning

confidence: 99%

“…However, they and others have found that these changes were based on oxidative modifications of fibrinogen. (64,66) Oxidative stress is common in LC, (71) and fibrinogen is very susceptible to oxidative changes. (72) Thus, oxidative modifications of fibrinogen likely contribute to decreased clot permeability.…”

Section: Fibrinogenmentioning

confidence: 99%

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Hemostatic Alterations in Patients With Cirrhosis: From Primary Hemostasis to Fibrinolysis

et al. 2020

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In the setting of liver cirrhosis (LC), profound hemostatic changes occur, which affect primary hemostasis, coagulation, and fibrinolysis. They involve prohemorrhagic and prothrombotic alterations at each of these steps. Patients with cirrhosis exhibit multifactorial thrombocytopenia and in vitro thrombocytopathy, counterbalanced by increased von Willebrand factor. The resultant shift is difficult to assess, but overall these changes probably result in a rebalanced primary hemostasis. Concerning coagulation, the reduced activity of coagulation factors is counterbalanced by an increase in factor VIII (produced by liver sinusoidal endothelial cells), a decrease of the natural anticoagulants, and complex changes, including changes in circulating microparticles, cell-free DNA, and neutrophil extracellular traps. Overall, these alterations result in a procoagulant state. As for fibrinolysis, increased tissue-type and urokinase-type plasminogen activators, a relatively decreased plasminogen activator inhibitor 1, and decreased levels of thrombin-activatable fibrinolysis inhibitor and α2-antiplasmin are counterbalanced by decreased plasminogen and a decreased fibrin clot permeability. Whether and how these changes shift fibrinolysis remains to be determined. Overall, the current consensus is that in patients with cirrhosis, the hemostasis is shifted toward a procoagulant state. We review the published evidence for the concept of LC as a prothrombotic state, discuss discordant data, and highlight the impact of the underlying cause of LC on the resultant imbalance. (Hepatology 2020;71:2135-2148). Primary HemostasisChanges of primary hemostasis in patients with LC are shown in Table 1.Abbreviations: ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 repeats 13;Hepatology, June 2020 ZERMATTEN ET AL. 2136pRoHeMoRRHagIC CHaNgeS thrombocytopenia Thrombocytopenia (platelets <150 × 10 9 /L) occurs in up to 78% (1) of patients with LC, moderate thrombocytopenia (platelets 50-75 × 10 9 /L) occurs in approximately 13%, (2) and severe thrombocytopenia (platelets <50 × 10 9 /L) occurs in 1% to 2%. (3) Decreased production and increased clearance of platelets are both involved in LC-associated thrombocytopenia ( Fig. 1). Indeed, reticulated/immature platelets and glycocalicin (proteolytic extracellular fragment of glycoprotein 1b), which are markers of platelet production, are decreased in LC. (4) However, reticulated/ immature platelet fraction and glycocalicin index, which are markers of platelet turnover, are increased in patients with LC versus healthy donors (4,5) and in thrombocytopenic versus non-thrombocytopenic patients with LC. (4,6) Moreover, the mean platelet survival is decreased in LC, (7) indicating an increased platelet turnover. Differences across LC causes are possible. Indeed, reticulated platelets are increased in hepatitis C virus (HCV)-induced LC and decreased in alcohol-induced LC and hepatitis B virus (HBV)induced LC. (5) DeCReaSeD pRoDUCtIoN oF plateletSDecreased production is due to decre...

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Section: Fibrinogenmentioning

confidence: 99%

Section: Fibrinogenmentioning

confidence: 99%

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Hemostatic Alterations in Patients With Cirrhosis: From Primary Hemostasis to Fibrinolysis

et al. 2020

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“…The proteins were resolved by the native PAGE using 8 % gel and transferred on the poly(vinylidene fluoride) membrane (PVDF). Protein carbonyls were derivatised in situ using dinitrophenylhydrazine (DNP) and immunoblotted using anti-DNP antibody [17,18].…”

Section: Investigation Of the Protective Effect Of Bilirubin Against mentioning

confidence: 99%

Characterisation and the effects of bilirubin binding to human fibrinogen

Gligorijević

Minić

Robajac

et al. 2019

International Journal of Biological Macromolecules

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Fibrinogen, a protein involved in blood coagulation, is very susceptible to oxidation. Oxidation alters its function and usually makes it more thrombogenic. Bilirubin, an end-product of the haem degradation in vertebrates, is known for its antioxidant properties. The present paper describes interaction between fibrinogen and bilirubin, and the influence of bilirubin on the formation of fibrin and protection against oxidation. The binding constant of 4.5 x 10 4 M-1 was determined for the fibrinogen/bilirubin complex at 37 °C. There is no change in secondary and tertiary structure of fibrinogen or its thermal stability upon bilirubin binding. The binding site of fibrinogen is not stereospecific for bilirubin and is able to accommodate both bilirubin conformers. A change in absorption maximum of bilirubin occurs upon its interaction with fibrinogen, suggesting an alteration in the conformation of bilirubin to the more cyclic one. Bilirubin exerts antioxidant effect on fibrinogen, preventing its carbonylation and aggregation. The presence of bilirubin induces the formation of fibrin with thicker fibres, as assessed by the coagulation assay. Fibrinogen and bilirubin interact at physiological concentrations, bilirubin may act as an antioxidant for fibrinogen and may modulate an important event in haemostasis, which altogether suggests possible physiological relevance of this interaction.

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“…Altered glycosylation affects fibrinogen properties in hepatic diseases [ 9 , 10 ] and the present study aimed to examine fibrinogen glycosylation in patients with ESRD-PD, as that may help in better understanding of the mechanisms underlying fibrinogen-related changes, and possibly assist in the therapeutic approach. Lectin-based protein microarray and lectin blotting were applied to define glycan structures on fibrinogen.…”

Section: Introductionmentioning

confidence: 99%

Fibrinogen Fucosylation as a Prognostic Marker of End-Stage Renal Disease in Patients on Peritoneal Dialysis

Baralić¹,

Gligorijević

Brković

et al. 2020

Biomolecules

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Glycosylation may strongly affect protein structure and functions. A high risk of cardiovascular complications seen in patients with end-stage renal disease (ESRD) is, at least partly associated with delayed clot formation, increased clot strength, and delayed cloth lysis. Taking into consideration that fibrinogen mediates these processes, we isolated fibrinogen from the plasma from patients with ESRD on peritoneal dialysis (ESRD-PD), and examined glycosylation of native fibrinogen and its subunits by lectin-based microarray and lectin blotting. Compared to healthy controls, fibrinogen from patients had increased levels of A2BG2 and decreased levels of FA2 glycan. The distribution of glycans on individual chains was also affected, with the γ chain, responsible for physiological functions of fibrinogen (such as coagulation and platelet aggregation), being most prone to these alterations. Increased levels of multi-antennary N-glycans in ESRD-PD patients were also associated with the type of dialysis solutions, whereas an increase in the fucosylation levels was strongly related to the peritoneal membrane damage. Consequently, investigation of fibrinogen glycans can offer better insight into fibrinogen-related complications observed in ESRD-PD patients and, additionally, contribute to prognosis, choice of personalised therapy, determination of peritoneal membrane damage, and the length of utilization of peritoneum for dialysis.

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Structural changes of fibrinogen as a consequence of cirrhosis

Cited by 13 publications

References 55 publications

Hemostatic Alterations in Patients With Cirrhosis: From Primary Hemostasis to Fibrinolysis

Hemostatic Alterations in Patients With Cirrhosis: From Primary Hemostasis to Fibrinolysis

Characterisation and the effects of bilirubin binding to human fibrinogen

Fibrinogen Fucosylation as a Prognostic Marker of End-Stage Renal Disease in Patients on Peritoneal Dialysis

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